Project Summary/Abstract Insulin resistance (IR) is central to the development of type 2 diabetes and dyslipidemia; however, there is no single phenotype of the insulin resistant patient. This phenotypic heterogeneity is reflected in clinical practice as variable manifestations of metabolic disease and variable response to both glucose lowering and triglyceride lowering agents (such as fibrates and fish oil). A precision medicine approach, wherein an understanding of the heterogeneity of disease is leveraged to target therapies to an individual patient?s pathology, requires an understanding of this heterogeneity of disease. Notably, among equally obese patients, some are globally insulin resistant, others insulin sensitive, and some demonstrate tissue specific IR. Thus, the mechanisms driving increased triglyceride production an any particular patient may depend on the patient?s pattern of tissue specific insulin resistance, with de novo lipogenesis predominating in the setting of skeletal muscle insulin resistance, and esterification of preformed fatty acids predominating in the setting of adipose insulin resistance. The overarching aim of this proposal is to build a mechanistic knowledge base to identify and optimize therapy for discrete subgroups of IR. To achieve this goal, Dr. Vatner aims to: 1) elucidate the pathways that support hepatic de novo lipogenesis (DNL) in rodent models of hepatic insulin resistance; 2) quantify the discrete pathways by which adipose and muscle insulin resistance promote hepatic triglyceride production; and 3) assess how differences in adipose and muscle insulin resistance in humans impact on the mechanisms underlying hepatic triglyceride synthesis. To achieve these goals, studies in both rodents and humans will be critical. Rodent models that exhibit different tissue specific patterns of insulin resistance will be used, including high fat diet fed mice, insulin receptor T1160A mutant mice, Tbc1d4p.Arg684Ter mutant mice, Mkr mice (mice with skeletal muscle specific resistance to insulin and IGF1), and adipose Pde3b knockout mice. Human subjects with different patterns of tissue specific insulin resistance will be studied. Stable isotope tracer techniques will be used to assess contributions of de novo lipogenesis and esterification of preformed fatty acids to triglyceride synthesis. Standard and cutting-edge molecular biology tools, including chromatin immunoprecipitation, quantitative PCR, RNA-Seq, and immunoblotting, will be used to delineate the molecular pathways playing key roles in the regulation of hepatic triglyceride production. The key subject of interest in this proposal is the clinical heterogeneity of hypertriglyceridemia in the setting of insulin resistance; studies using pharmacologic interventions (SGLT2 inhibition, inhibition of adipose lipolysis) and exercise interventions will directly address this clinical heterogeneity.